ADAR2 regulates RNA stability by modifying access of decay-promoting RNA-binding proteins

Anantharaman, Aparna; Tripathi, Vidisha; Khan, Abid; Yoon, Je‐Hyun; Singh, Deepak Kumar; Gholamalamdari, Omid; Guang, Shuomeng; Ohlson, Johan; Wahlstedt, Helene; Öhman, Marie; Jantsch, Michael F.; Conrad, Nicholas K.; Ma, Jian; Gorospe, Myriam; Prasanth, Supriya G.; Prasanth, Kannanganattu V.

doi:10.1093/nar/gkw1304

Cited by 37 publications

(56 citation statements)

References 63 publications

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“…2A,B). Taken together, our current results and previous findings show that both ADAR1 and ADAR2 edit specific sites within Ctn RNA [40].…”

Section: Resultssupporting

confidence: 91%

“…A,C). Recently, we have shown that ADAR2 edits several of the adenosines within the FwR and IR2 . We aimed to determine if ADAR1 too contributes to A‐to‐I editing of Ctn RNA .…”

Section: Resultsmentioning

confidence: 99%

“…Numbers below each blot indicate ImageJ quantitation of decrease in Flag‐ ADAR 2 levels in RNA se‐treated relative to RNA se‐untreated. (C) Pie‐chart comparing different types or degrees of editing observed in the RNA ‐seq data of WT and Adar2 ‐ KO MEF s . Heat map shows the degrees of editing of substrates that do not exhibit a complete loss of editing in absence of ADAR 2 (representing potential overlapping ADAR 1 and ADAR 2 substrates) as observed in the RNA ‐seq data of WT and Adar2 ‐ KO MEF s .…”

Section: Resultsmentioning

confidence: 99%

“…We have previously reported a novel function for ADAR2 in A-to-I editing and promoting the stability of nuclear-retained Cat2 transcribed nuclear RNA (Ctn RNA) by antagonizing the interaction between Ctn RNA and the decay-promoting RNA-binding proteins ELAVL1/HuR and PARN [poly(A)-specific ribonuclease] deadenylase [40]. In the present study, we show that like ADAR2, ADAR1 also edits and stabilizes Ctn RNA, suggesting that Ctn RNA requires both ADAR1 and ADAR2 for its stability.…”

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confidence: 99%

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RNA‐editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA

et al. 2017

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Adenosine Deaminases acting on RNA (ADARs) are proteins that catalyze widespread A-to-I editing within RNA sequences. We recently reported that ADAR2 edits and stabilizes nuclear-retained Cat2 transcribed nuclear RNA (Ctn RNA). Here, we report that ADAR1 coordinates with ADAR2 to regulate editing and stability of Ctn RNA. We observe an RNA-dependent interaction between ADAR1 and ADAR2. Furthermore, ADAR1 negatively regulates interaction of Ctn RNA with RNA-destabilizing proteins. We also show that breast cancer (BC) cells display elevated ADAR1 but not ADAR2 levels, compared to non-tumorigenic cells. Additionally, BC patients with elevated levels of ADAR1 show low survival. Our findings provide insights into overlapping substrate preferences of ADARs and potential involvement of ADAR1 in breast cancer.

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“…2A,B). Taken together, our current results and previous findings show that both ADAR1 and ADAR2 edit specific sites within Ctn RNA [40].…”

Section: Resultssupporting

confidence: 91%

“…A,C). Recently, we have shown that ADAR2 edits several of the adenosines within the FwR and IR2 . We aimed to determine if ADAR1 too contributes to A‐to‐I editing of Ctn RNA .…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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RNA‐editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA

et al. 2017

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“…However, recent reports show that HuR can destabilize specific target transcripts in C2C12 myoblasts (61) and other cell types (62,75,76). Our data demonstrate that ARE3 and ARE4 negatively regulate Pabpn1 expression in C2C12 myotubes, and that HuR binds specifically to ARE4 in a biochemical assay.…”

Section: Discussionmentioning

confidence: 99%

Post-transcriptional regulation of Pabpn1 by the RNA binding protein HuR

Phillips

Banerjee

Sánchez

et al. 2018

Nucleic Acids Research

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RNA processing is critical for proper spatial and temporal control of gene expression. The ubiquitous nuclear polyadenosine RNA binding protein, PABPN1, post-transcriptionally regulates multiple steps of gene expression. Mutations in the PABPN1 gene expanding an N-terminal alanine tract in the PABPN1 protein from 10 alanines to 11–18 alanines cause the muscle-specific disease oculopharyngeal muscular dystrophy (OPMD), which affects eyelid, pharynx, and proximal limb muscles. Previous work revealed that the Pabpn1 transcript is unstable, contributing to low steady-state Pabpn1 mRNA and protein levels in vivo, specifically in skeletal muscle, with even lower levels in muscles affected in OPMD. Thus, low levels of PABPN1 protein could predispose specific tissues to pathology in OPMD. However, no studies have defined the mechanisms that regulate Pabpn1 expression. Here, we define multiple cis-regulatory elements and a trans-acting factor, HuR, which regulate Pabpn1 expression specifically in mature muscle in vitro and in vivo. We exploit multiple models including C2C12 myotubes, primary muscle cells, and mice to determine that HuR decreases Pabpn1 expression. Overall, we have uncovered a mechanism in mature muscle that negatively regulates Pabpn1 expression in vitro and in vivo, which could provide insight to future studies investigating therapeutic strategies for OPMD treatment.

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All I's on the RADAR: role of ADAR in gene regulation

Shevchenko

Morris

2018

FEBS Letters

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Adenosine to inosine (A-to-I) editing is the most abundant form of RNA modification in mammalian cells, which is catalyzed by adenosine deaminase acting on the double-stranded RNA (ADAR) protein family. A-to-I editing is currently known to be involved in the regulation of the immune system, RNA splicing, protein recoding, microRNA biogenesis, and formation of heterochromatin. Editing occurs within regions of double-stranded RNA, particularly within inverted Alu repeats, and is associated with many diseases including cancer, neurological disorders, and metabolic syndromes. However, the significance of RNA editing in a large portion of the transcriptome remains unknown. Here, we review the current knowledge about the prevalence and function of A-to-I editing by the ADAR protein family, focusing on its role in the regulation of gene expression. Furthermore, RNA editing-independent regulation of cellular processes by ADAR and the putative role(s) of this process in gene regulation will be discussed.

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ADAR2 regulates RNA stability by modifying access of decay-promoting RNA-binding proteins

Cited by 37 publications

References 63 publications

RNA‐editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA

RNA‐editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA

Post-transcriptional regulation of Pabpn1 by the RNA binding protein HuR

All I's on the RADAR: role of ADAR in gene regulation

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